tbuckley/cabot-search huggingface dataset:
Prognostic value of circulating Epstein-Barr virus DNA level post-induction chemotherapy for patients with nasopharyngeal carcinoma: A recursive partitioning risk stratification analysis.
Authors: Fang-Fang Kong, Guang-Sen Pan, Meng-Shan Ni, Cheng-Run Du, Zhen Zhang, Chaosu Hu, Hong-Mei Ying
Journal: Journal of Clinical Oncology (2023)

6024 Background: To evaluate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level post-induction chemotherapy (IC) for patients with nasopharyngeal carcinoma (NPC). Methods: A total of 893 newly diagnosed NPC patients treated with IC were retrospectively reviewed. The recursive partitioning analysis (RPA) was performed to construct a risk stratification model. The receiver operating characteristic (ROC) analysis was applied to determine the optimal cut-off value of EBV DNA and compare the predictive validity. Results: Post-IC EBV DNA levels and overall stage were independent predictors for distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). The RPA model base on post-IC EBV DNA and overall stage categorized the patients into three distinct risk groups: RPA I (low-risk: stage II-III and post-IC EBV DNA &lt; 200 copies/mL), RPA II (median-risk: stage II-III and post-IC EBV DNA≥200 copies/mL, or stage IVa and post-IC EBV DNA &lt; 200 copies/mL), and RPA III (high-risk: stage IVa and post-IC EBV DNA≥200 copies/mL), with 3-year PFS of 91.1%, 82.6%, and 60.2%, respectively (p &lt; 0.001). The DMFS and OS rates in different RPA groups were also distinct. ROC analysis showed that the RPA model had superior predictive efficacy than the overall stage. Conclusions: Plasma EBV DNA level post-IC was a robust prognostic biomarker for NPC. We developed a risk stratification model that provides improved DMFS, OS, and PFS prediction over the 8th edition of the TNM staging system by integrating the post-IC EBV DNA level and the overall stage.
Efficacy and safety of switching other tyrosine kinase inhibitors to regorafenib combined with primary PD-1 antibodies in patients with hepatocellular carcinoma.
Authors: Shida Pan, Yingying Yu, Siyu Wang, Qin Qiu, Yingjuan Shen, Luo Yang, Xiaomeng Liu, Junqing Luan, Fanping Meng
Journal: Journal of Clinical Oncology (2023)

e14612 Background: Currently, formal tyrosine kinase inhibitors (TKIs) such as sorafenib or lenvatinib in combination with PD-1/PD-L1 immune checkpoint inhibitor had achieved promising results in patients with hepatocellular carcinoma (HCC). However, a portion of patients experienced drug-resistant tumor progression and/or severe adverse events associated with TKIs during the course of treatment, resulting in unfavorable disease control and poorer overall survival. Therefore, a better medication strategy is urgently needed in aim to improve the prognosis of these patients who experienced discontinuing medication of TKIs. Methods: We reviewed the medical data of 23 HCC patients with disease progression after received sorafenib or lenvatinib combined with PD-1 antibodies from Jan Feb 2020 to Sep 2021 at the Fifth Medical Center of PLA General Hospital in China. These patients had switched to regorafenib PO for 3 weeks on/1 week off combined with primary PD-1 antibodies after experienced tumor progression and/or severe adverse events with respect to sorafenib or Lenvatinib. All patients were followed up regularly. Changes of tumor lesions, survival data and adverse events (AEs) were detailed recorded after switched. All AEs were evaluated according to the CTCAE v5. Results: Initially, 20 (87.0%) patients were treated with lenvatinib and 3 (13.0%) patients were treated with sorafenib before switched to regorafenib. Of all patients, tumor progression caused 15 (65.2%) switching and severe AEs caused 8 (34.8%) switching, and the initial daily dose of regorafenib were 80mg (95.6%) and 40 mg (4.4%), respectively. Before switched to regorafenib, the most common mild AEs were hypertension, hypothyroidism and granulocytopenia, and the most common severe AEs were rash, hepatitis, and lung infections. In contrast, the most common AEs was mild hoarseness after switched to regorafenib. During the follow-up, 12 (52.2%) patients died, 3 (13.0%) patients lost and 8 (34.8%) patients sustained survival. The overall median survival time (MST) was 22.47 months [95% confidence interval (CI): 2.98 months to 41.96 months], the MST after switched to regorafenib was 10.53 months (95% CI: 0.257 months to 20.81 months). Of note, size of tumor lesion decreased in 7 (30.4%) patients and increased in 3 (13.0%) patients, and the other 13 (56.6%) patients could not be evaluated due to incomplete data after switching to regorafenib. Conclusions: For patients who are resistant to other TKIs, switching to regorafenib showed good efficacy and manageable safety. Therefore, this treatment protocol can be considered as a potential treatment for patients without clinical benefits after first or second-line combination therapy.
First report of tumor-informed circulating tumor DNA in fibrolamellar carcinoma in adolescents and young adults: 51 patients.
Authors: Elise McKenna, Paul Kent, Jordan C Tasse, Erik Schadde, Oliver M Fisher, Abhinav Humar, Tom Kato, Jessica Ellison, Darrell Yamashiro, Albert Cornelius
Journal: Journal of Clinical Oncology (2023)

3034 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare form of primary liver cancer (50-200 cases/year), unrelated to hepatocellular carcinoma. The only established standard of care is surgery. However, recurrence is at least 80%, even with R0 surgery, suggesting that FLC is best thought of as a systemic disease instead of a surgical disease. Systemic therapies in retrospective studies of more than 25 show immunotherapy and chemotherapy combinations have promise. Circulating “tumor-informed” tumor DNA (ctDNA) is a tool for tracking microscopic systemic disease, serving as a marker of systemic involvement, has shown success in management of other cancers. FLC has never been studied using this technology. Our retrospective study of 51 patients over a 2.5-year period is the first attempt to understand if ctDNA can be helpful in the management of FLC. Methods: All patients consented to blood draws on a 1-3 monthly basis, according to the company (Signatera) protocol. All patients had regular imaging reviewed by the FibroFighters Foundation National Tumor Board. Complete response (CR), Partial response (PR) (&gt; 30% decrease), Progressive Disease (PD) (&gt; 20% increase), and Stable Disease (SD) (neither PD/PR/CR) were recorded according RECIST 1.1. The imaging closest in time to the blood draw was used for correlation purposes. “Negative” is defined as a value = 0.00. “Positive” is defined as a value &gt; 0.00. Results: Fifty-one FLC patients (26M, 25F, median age 23, range 10-56), 92% stage (III/IV), consented to ctDNA “blood biopsies,” (n=226 samples, mean 4.4/patient, range 1-11). Negative values correlated with no evidence of disease (NED) on imaging 78% of the time, positive values with disease 94% [PPV/NPV/sens/spec of 0.78/0.94/0.93/0.81]. NPV and sens increased to almost 100% with a ctDNA threshold of &gt; 1.0 at the expense of a lower PPV and spec. However, consecutive negative ctDNA values correlated with radiologic NED 86% [PPV/NPV/sens/spec = 0.86/0.84/0.77/0.91] without a single PD in this cohort (n=64). A “downward trend or slope” on consecutive values predicted Objective Response (CR+PR) and Disease Control (CR+PR+SD) at 68% and 96% [PPV/NPV/sens/spec of 0.68/0.49/0.36/0.78 and 0.96/0.26/0.36/0.94, respectively], while an “upward trend” performed less well to predict relapse [PPV/NPV/sens/spec = 0.54/0.98/0.94/0.81]. Conclusions: In this first exploration of 51 young FLC patients, and 226 tissue-informed cell free ctDNA data points, “Positive” and “Negative” values overall performed well for predicting RECIST 1.1 “disease” or “NED” respectively, especially for consecutive values of zero, where no progressions were observed in 64 distinct FLC scenarios. A downward trend or “slope” performed better than an upward trend to predict objective response (PR+CR) versus relapse (PD).
Treatment response prediction with circulating tumor cell-derived organoids for soft tissue sarcoma.
Authors: Yang-Wei Liu, Thierry Burnouf, Chia-Yau Chang, Shu-Huey Chen, Yin-Ju Chen, Yi-Hsuan Chen, Wan-Ling Ho, Yu-Mei Liao, Pei-Chin Lin, Yen-Lin Liu, James S. Miser, Jinn-Li Wang, Peng Yuan Wang, Shih-Chung Wang, Tai-Tong Wong, Shih-Pei Wu, Yuan-Hung Wu, Jeng-Fong Chiou, Long-Sheng Lu
Journal: Journal of Clinical Oncology (2023)

e23521 Background: Pharmacologic treatment for soft tissue sarcoma (STS) remains challenging. There is a lack to predict treatment responses to chemotherapy or targeted therapy to oncologic drivers. We hypothesize that circulating tumor cells may enrich cancer initiating cells and represent a window to probe personalized drug treatment response. In this study, we test if drug sensitivity profile of short-term culture of tumor organoids derived from circulating tumor cells (CTCs) correlates to clinical treatment response. Methods: From April 2019 to December 2020, 50 patients with biopsy-confirmed STS, who had either recurrent or metastatic tumors, were enrolled in a prospective observational study in Taipei Medical University Hospital. The median age of the patients was 47, and the top 3 diagnoses were leiomyosarcoma, aggressive fibromatosis and rhabdomyosarcoma. 74% of patients had metastatic diseases at the time of blood collection. Fifty-five blood samples were collected and processed for CTC organoid culture and drug sensitivity analysis (EVASelect, CancerFree Biotech, Taipei, Taiwan), which involves culturing nucleated blood cells on a binary colloid crystal-coated surface. Clinical response was evaluated using RECIST criteria 3 months after blood collection. The relationship between CTC viability and clinical response was analyzed using a contingency table and Chi-square analysis. Results: The success rate of CTC expansion was 87.2% (48/55), as defined by ATP abundance higher than 3000 U2OS cells after 18 days of culture. Clinical information from 32 of the 50 cases was eligible for analysis, and the results showed that CTC viability at a 70% cutoff correlated with clinical disease control at 3 months after blood collection. The odds ratio, sensitivity, specificity, and diagnostic accuracy were 12 (p = 0.036), 92.3%, 50%, and 79%, respectively. A demonstration of the interaction between this research and the Molecular Tumor Board (MTB) in the Taipei Medical University Healthcare System is presented through a case study of metastatic angiosarcoma and its correlation. Conclusions: The study highlights the potential of using CTC drug sensitivity as a biomarker for precision medicine in STS, despite limitations such as small sample size, short follow-up, and disease and treatment heterogeneity. Advancements in gene-based precision medicine have been made in the past decade, but only a small number of STS patients have seen benefits from it. This emphasizes the need for further research to thoroughly evaluate the potential of CTC drug sensitivity as a predictive biomarker in clinical practice. Key words: soft tissue sarcoma; circulating tumor cells; liquid biopsy; predictive biomarker; precision medicine.
Circulating levels of the pro-inflammatory monomeric isoform of C-reactive protein (mCRP) correlate with inflammatory markers in patients with stage II-III colon cancer.
Authors: Anniken Joerlo Fuglestad, Paula Anna Bousquet, Anne Helene Køstner, Sebastian Meltzer, Anne Hansen Ree, Rafael Fernandez-Botran, Christian Kersten
Journal: Journal of Clinical Oncology (2023)

e15641 Background: Tumor-promoting inflammation is an established hallmark of cancer. C-reactive protein (CRP) is one of the most studied negative prognostic markers of the systemic inflammatory response (SIR) and known to be implicated in detrimental immune responses. Circulating CRP, as measured in routine practice, is a pentameric structure (pCRP). However, when pCRP binds to activated membranes, the protein dissociates into subunits termed monomeric CRP (mCRP). Pro-inflammatory characteristics of mCRP have been reported to be stronger than for pCRP. While a role for mCRP in cancer has been proposed, the circulating level of mCRP has never been investigated in cancer patients. Our aim was to detect and quantify plasma mCRP of patients diagnosed with stage II-III colon cancer (CC) and investigate possible correlations with other inflammatory markers. Methods: 40 patients treated for stage II-III CC between 2012 and 2015 at Sorlandet Hospital, Norway, were included in the study. 20 patients had pCRP level &lt; 10 mg/L and 20 patients had pCRP &gt; 10 mg/L, the latter interpreted as presence of SIR. Levels of pCRP and albumin were captured at the time of diagnosis. Pre-operative mCRP and the cytokines IL-6, IL-8 and TNFa were all measured using EDTA plasma samples. Pre-operative mCRP levels were measured by a specific ELISA employing reagents kindly provided by Drs. L. Potempa and I. Rajab (Roosevelt University, Schaumburg, IL). Results: Of the 40 patients, 47.5% were female, 57.5% had right-sided primary tumor and 50.0% were stage III. Median values (min-max) were for mCRP 2.55 ng/mL (0.00-10.9), pCRP 9.95 mg/L (0.50-136), IL-6 5.10 pg/mL (2.60-25.1), IL-8 4.95 pg/mL (0.40-32.4), TNFa 5.90 pg/mL (3.10-29.5) and albumin 40 g/L (29.0-46.0). Conclusions: To the authors’ knowledge, this is the first time mCRP has been reported in systemic circulation of cancer patients. Our study shows plasma mCRP to be quantifiable in CC patients, albeit at very low levels. This may be due to its reduced aqueous solubility and supports the notion of mCRP as a circulating particle-bound or tissue-associated isoform. However, despite low circulating mCRP levels and a small number of patients, mCRP still correlated with other well-known SIR markers with proven negative prognostic value in cancer patients, supporting its potential role as a pro-inflammatory player in CC. Further studies correlating SIR with circulating and tissue-bound mCRP are currently being performed. [Table: see text]
Immune related adverse events (irAEs) in patients with solid tumors and advanced chronic kidney disease (CKD) receiving checkpoint inhibitors (CPIs).
Authors: Dalia Kaakour, Elham Vosoughi, Brian Warnecke, Omid Yazdanpanah, Arash Rezazadeh, Jennifer Brooke Valerin, Nataliya Mar
Journal: Journal of Clinical Oncology (2023)

2650 Background: Randomized controlled trials evaluating CPIs in the management of solid tumors have typically excluded patients with advanced CKD and end-stage renal disease (ESRD). Limited available data evaluating the safety of CPI use in this patient population demonstrated a similar incidence of irAEs in patients with advanced CKD compared to those with normal or mildly impaired renal function, with majority of irAEs being grade 1 or 2. CPIs are not modified by dialysis due to their molecular size and, as such, do not require renal dosing. Methods: We performed a retrospective analysis of patients over 18 years of age with solid tumors and advanced CKD, who received CPIs at the University of California Irvine from 1/2015 to 6/2021. Advanced CKD was defined as glomerular filtration rate (GFR) less than 60 ml/min. Patients must have received at least one dose of a PD-1/PD-L1 or CTLA-4 inhibitor as a single-agent or in combination with another therapy. Patients were stratified by severity of CKD, including CKD3 (GFR of 30-59 ml/min), CKD4 (GFR of 15-29 ml/min), and CKD 5/ESRD (GFR less than 15 ml/min). Results: A total of 32 patients were included, 24 (75.00%) with CKD3, 6 (18.25%) with CKD4, and 2 (6.25%) with CKD5/ESRD. 10 (31.25%) patients were female and 22 (68.75%) were male. Median age was 73.5 years [range: 26 to 98]. 22 (68.75%) received CPI monotherapy and 10 (31.25%) received a combination of CPI with another agent. After initiation of CPI therapy, 16 (50.00%) patients experienced an irAE, with a total of 23 unique irAEs due to some patients experiencing multiple irAEs. In patients with irAEs, 13 (81.25%) received CPI monotherapy and 3 (18.75%) received CPI combined with another agent. In patients with CKD3, CKD4, and CKD5/ESRD, 14 (87.50%), 2 (12.60%), and 0 (0.00%) experienced irAEs, respectively. Types of irAEs observed are listed, with the most common being colitis in 6 (26.1%) patients, endocrinopathies in 4 (17.39%) patients, and dermatologic in 4 (17.39%) patients. 18 (78.26%) of unique irAEs were grade 1 or 2, while 5 (21.74%) were grade 3 or higher. 10 (43.48%) of irAEs were managed with steroids as per physician discretion, 8 (80.00%) with CKD3 and 2 (20.00%) with CKD4. Conclusions: The safety of CPIs in patients with solid tumors and advanced CKD has not been rigorously evaluated. Recognizing the small sample size and retrospective nature of this dataset, the incidence and type of irAEs in patients with advanced CKD appears similar to that of patients with normal renal function or mild renal impairment. More prospective data in this population is needed, particularly in patients with CKD5/ESRD. Types of irAEs in patients with advanced CKD. [Table: see text]
The Ohio State University Guardant Shield Colorectal Cancer Screening Project.
Authors: Peter Stanich, Cecilia R DeGraffinreid, Chasity M Washington, Oindrila Bhattacharyya, Angela Lontoc, Electra D. Paskett
Journal: Journal of Clinical Oncology (2023)

TPS3626 Background: Asymptomatic screening is an effective method for detecting early cancers when prognosis strongly depends on stage at time of diagnosis. Unscreened individuals often have a basic understanding of the importance and availability of colorectal cancer (CRC) screening but have concerns regarding the collection method of the currently available stool-based options or the invasiveness of direct visualization options that deter test completion. We hypothesize that offering a blood-based CRC screening test during a routine healthcare visit can increase screening adherence, especially within hard-to-reach populations and those hesitant about completing CRC screening. Methods: The Ohio State University Guardant Shield Colorectal Cancer Screening Project (NCT05716477) is a prospective study in the United States designed to recruit individuals who are currently engaging with mobile health clinics and are not up to date with CRC screening, with the aim of improving health in hard-to-reach populations. The study’s primary objective is to evaluate the acceptance of a commercially available blood-based CRC screening test (Shield, Guardant Health, USA) in individuals aged 45-84, who have existing appointments with a mobile health clinic, and are not up to date with guideline recommended CRC screening. The study team screens for eligibility criteria before the appointment and reaches out to the individual to begin the informed consent process. Positive blood-based test results will be triaged to colonoscopy for further evaluation. A post-study survey will be administered to consented individuals aimed to collect data on CRC screening knowledge which will be correlated to patient demographics and uptake. Acceptance will be defined as those approached and with completed specimen collection. Progress: The study initiated on October 25, 2022, with the first patient enrolled on December 20, 2022. Enrollment is expected to continue with a target enrollment of 300 individuals. Clinical trial information: NCT05716477 .
Analysis of androgen receptor dynamics through immunofluorescent staining of circulating tumor cells in castration-resistant prostate cancer.
Authors: Ethan Barnett, Santosh Gupta, Tatiana Erazo, Ernest Lam, Emily Carbone, Michelle Zanone, Lucy Nystrom, Ria N Gajar, Rick Wenstrup, Howard I. Scher
Journal: Journal of Clinical Oncology (2023)

e17021 Background: Prostate adenocarcinomas are initially dependent on the androgen receptor (AR) for growth and proliferation. Androgen synthesis inhibitors and AR antagonists are the most commonly used first line treatments in metastatic prostate cancer, but these agents are not curative and virtually all tumors progress to a castration resistant state often associated with AR amplification (AR amp ) and overexpression. Small molecule AR degraders designed to overcome AR amp /overexpression and other AR alterations associated with resistance are now in clinical development. In parallel, it is important to identify and validate biomarkers that predict sensitivity and inform treatment selection. Methods: CTC samples collected at progression from 114 men with metastatic castration resistant prostate cancer were stained for CK, DAPI, CD45, and AR. AR cRatio (ratio between a cell’s immunofluorescent [IF] intensity and the median IF intensity across all cells) was quantified for each CTC. Low-pass whole genome sequencing (lpWGS) was performed on candidate CK-positive (CK+) CTCs to generate copy number profiles. Cohen’s kappa was used to evaluate the relationship between AR copy number and IF at the single cell level. Dynamics in high AR expressing (AR high ) CTCs were analyzed separately in a longitudinal cohort of patients (n = 18) from whom CTCs were collected at baseline, early on-treatment (4-12 weeks), and at progression on their 1 st AR signaling inhibitor (1L-ARSI). Results: lpWGS was performed on 726 CK+ CTCs, of which 23% (170) were AR amp and 27% (195) were AR high (AR cRatio ≥ 3). Fifty-six percent (96/170) of CTCs with AR amp were AR high . Overall, a fair agreement was observed between AR copy number and IF (76.1% agreement; k = 0.37, 95%CI = 0.29 – 0.44). At baseline prior to 1L-ARSI, the median CK+ CTC burden was 7.9 CTC/mL (IQR: 1.3 – 10.5). One or more AR high CTC was detected in 28% (5/18) of patients, but no patient had more than 0.7 AR high CTCs per mL of blood. AR high CTCs were not observed in early on-treatment samples. At progression, the median CTC burden was 2.3 CTC/mL (IQR: 0.9 – 9.45) and, despite lower CTC burden, the emergence of a substantial (≥1 CTC/mL) AR high CTC subpopulation was observed in 17% (3/18) of patients. In samples with ≥1 detected CTC, the mean AR cRatio was 1.106 and 1.777 at baseline and progression, respectively. Conclusions: AR protein can be measured in CTCs with IF staining and is supported by the agreement with data from lpWGS. AR high CTC subpopulations can be detected at baseline for 1L-ARSI, but these cells were all cleared from circulation after 4-12 weeks of therapy. In a subset of patients at progression, resistance appears at least partially attributable to selection for AR high CTC subclones. [Table: see text]